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Abstract Introduction Obstructive sleep apnea (OSA) is associated with cardiovascular conditions when left untreated. While PAP therapy is the first-line treatment for OSA, real-world evidence on its impact in cardiovascular-related events is limited. This study assessed the relationship between long-term PAP adherence and CVRHU in a national OSA cohort. Methods This retrospective study analyzed insurance claims linked with objective PAP usage data from patients diagnosed with OSA who initiated PAP between 2015-2021. Two-year PAP adherence was defined as adherent, intermediate, or non-adherent based on US Medicare criteria. CVRHU was defined as emergency room (ER) visits, hospitalizations, or either (“serious cardiovascular-related event”), with primary diagnoses of stroke, heart failure, coronary artery disease, arrhythmia, cardiomyopathy, or hypertension. Covariates included demographics, obesity, comorbidities, healthy behaviors, and prior healthcare use. Inverse probability of treatment weighting was used to evaluate associations between adherence and CVRHU. Results The sample (n=377,830) was 42% female, mean age 51.7±11.9 years. Over two years, 75% of patients were at least intermediately adherent to PAP (25% non-adherent). Adherent patients were significantly less likely to have a serious cardiovascular-related event compared to non-adherent (4.09% vs 5.22%, P< 0.001), representing a 22% lower risk of having an event (RR: 0.78, 95% CI: 0.75-0.81). Intermediate adherence outcomes fell between adherent and non-adherent groups, with lower rates of cardiovascular-related ER visits (3.34% vs 3.70%, P< 0.001), hospitalizations (1.90% vs 2.09%, P< 0.001), and serious cardiovascular-related events (4.77% vs 5.22%, P< 0.001) compared to non-adherent. Total healthcare costs per patient were significantly lower for adherent patients compared to non-adherent (year 1: $9,748 vs $10,861, P=0.014; year 2: $9,102 vs $9,847, P< 0.001). Associated costs aligned with the frequency of events, with adherent patients incurring significantly lower costs compared to intermediate and non-adherent patients in the first year and further reductions in year 2 (year 1: adherent: $182 vs intermediate: $230 vs non-adherent: $257, P< 0.001; year 2: adherent: $166 vs intermediate: $237 vs non-adherent: $267, P< 0.001). Conclusion This real-world study demonstrates the relationship between PAP adherence and reduced CVRHU in patients with OSA. These findings underscore the importance of strategies to enhance PAP adherence to improve long-term cardiovascular outcomes. Support (if any) ResMed